Project Summary Traumatic brain injury (TBI) continues to be a serious problem in society with 1.7 million occurrences annually in the United States. Currently there have been no neuroprotective drug trials to survive past Phase III clinical trials. Previous in vivo testing, involves injury models that are not clinically-relevant, do not include biological variability and are typically small animal models. There is a need to study impact-TBI in a gyrencephalic minipig model using a repeatable combined translation and rotation-input injury device. The specific aims of this study are to: 1) Determine the acute behavioral and pathologic effects of two impact-induced TBI severities in minipigs, 2) Determine whether the Gttingen or the Yucatan minipig is the more appropriate large animal model for impact-induced TBI using neuropathological, imaging, and behavioral techniques and to 3) Determine sex influences on acute behavioral and pathologic effects following impact-induced TBI. Complex MR imaging techniques and cognitive/behavioral tests will be used to measure changes compared to pre-injury assessments and longitudinally within the same animal to evaluate possible recovery caused by two impact severities. Histology will define the underlying damage compared to sham animals. Cognitive impairments and MR imaging changes can be related to underlying damage to make a link between noninvasive and invasive measurements. These measures can also help ease translation to clinical tools to improve diagnosis and intervention. Addressing biological variability by evaluating different minipig species and sex differences will help address some of the limitations in current preclinical models. Ultimately, developing a standardized preclinical model that produces clinically-relevant impact TBI in a gyrencephalic animal model will better measure drug safety and efficacy. In addition, a well-characterized model can give insight into new drug targets that were missed by previously used in-vivo models with non-realistic injury conditions.